Rabu, 3 Oktober 2012

Terapi sel dendritik

http://cancer.stanford.edu/research/immunology/dendritic.html

Dendritic cells (DCs) represent unique antigen-producing cells capable
of sensitizing T cells to both new and recall antigens. In fact, these cells
are the most potent antigen-producing cells. The goal of DC based cancer
immunotherapy is to use the cells to prime specific antitumor immunity through
the generation of effector cells that attack and lyse tumors.

DCs as Cancer Vaccines

The first attempt to use DCs as cancer vaccines in humans was made by Edgar Engleman and Ronald Levy (Program 6) here at
Stanford, who isolated DCs from patients with non-Hodgkin's lymphoma who had
failed conventional chemotherapy, loaded the cells with immunoglobulin idiotype
obtained from the patient's tumor, and reinjected the antigen-loaded cells back
into the patients. Remarkably, most of the treated patients developed T cell
mediated immune responses to their tumor-specific antigen and of the first six
patients, two had complete remissions.

Since then, a larger number of patients with non-Hodgkin's lymphoma have
been treated at Stanford with idiotype-pulsed DCs and the efficacy confirmed.
In addition, pilot clinical trials of antigen-pulsed DCs have been conducted at
Stanford in various types of cancer, including prostate cancer, colorectal
cancer, multiple myeloma, and non-small cell lung cancer. These studies, and
other studies carried out elsewhere, show that antigen-loaded DC vaccinations
represent a safe and promising form of immunotherapy for a wide range of
malignancies.

DC Loading and Activation

However, the current approaches are far from optimal in that many
patients treated with DC vaccines have failed to respond. Moreover, ex vivo manipulation
of DCs is time consuming and costly, requires the use of numerous cytokines and
exposes the patient to increased risk of infection. To avoid manipulation of
DCs in vitro and increase the potency of DC vaccination, Dr. Engleman's
group has been working on approaches to load and activate DCs in vivo.

By administering a DC growth factor, Fms like tyrosine kinase 3 Ligand (
Flt3L ), to tumor bearing mice, followed by subcutaneous injection of
oligodeoxynucleotides containing unmethylated CG motifs (CpG) together with a
defined tumor Ag, they were able to induce significant anti-tumor responses in
mice challenged with B16 melanoma.

The induction of a strong and durable immune response was dependent on
the accumulation in skin of high numbers of Flt3L -mobilized DCs which
facilitated their loading and activation with a local injection of a mixture of
tumor antigen and CpG. These results suggested that access of DCs to tumor
antigens, as well as the ability of these cells to mature, are critical for the
induction of an efficient immune response.

Uptake of Tumor Antigens

More recently the Engleman lab has attempted to increase the uptake of
tumor antigens by DCs, in vivo, by directing circulating DCs to tumors rather
than delivering exogenous tumor antigens to Flt3L mobilized DCs.
CCL20/macrophage inflammatory protein-3 a (MIP-3 chemokine, a potent
chemo-attractant for a subset of DCs in both humans and mice, was used alone or
in combination with CpG to activate tumoral DCs in mice.

Expression of CCL20 in the tumo r site attracted large numbers of circulating
DCs into the tumor mass, and in the case of CT26 (colorectal) tumors led to
complete tumor regression. Intratumoral CpG injections, in addition to CCL20,
were required to induce therapeutic immunity against B16 melanoma tumors.

In this model CpG overcame tumor mediated inhibition of DC activation
and enabled tumoral DCs to cross present tumor antigens to naïve CD8 T cells.
CpG activation of tumoral DCs alone was not sufficient to induce tumor
regression in either tumor model, nor was systemic delivery of Flt3 ligand,
which dramatically increased the number of circulating DCs but not the number
of tumoral DCs.

These results indicate that the number of tumoral DCs as well as the
tumor milieu determines the ability of tumor bearing hosts to mount an effective
anti-tumor immune response. The results also suggest that DCs can be
manipulated in vivo without delivery of defined tumor antigens to induce
a specific T cell mediated anti-tumor response and provide the basis for the
use of chemokines in DC-targeted clinical strategies.

Intratumoral Injections of
Naïve DCs

An additional approach under investigation by the Engleman lab involves
intratumoral injections of naïve DCs into tumors that have been treated with
either radiofrequency ablation or photodynamic therapy. The latter therapies
are effective locally but not systemically, and importantly, in tumor bearing
mice the combination of either treatment with intratumoral DCs can be curative.

These observations formed the basis of two recently approved INDs for
clinical trials that are being undertaken by Drs. Engleman, George Fisher (Program 9), and Wenru
Song (Program 6) for the treatment of pancreatic cancer and metastatic colorectal
cancer, respectively.

Dendritic Cell (DC) therapy represents a new and promising
immunotherapeutic approach for treatment of advanced cancer as well as for
prevention of cancer. As Dr. Harmon Eyre, the VP of Research at the AMA
commented: “Patients’ responses are far out of proportion to anything that any
current therapy could do”. For decades, cancer researchers have been interested
in immunologic treatments against cancer but with little progress. However,
recent advances lead to successful implementation of Dendritic Cell therapy
with reports of complete responses even in stage IV cancer patients who have
failed all other therapies. Dendritic Cell (DC) Therapy or so-called Dendritic
Cell vaccine is a newly emerging and potent form of immune therapy used to
treat cancer. To learn more about vaccine and Dendritic Cell therapy
for cancer, please read the following:

“Dendritic cells and immunity against cancer” by K. Palucka, H. Ueno1, J. Fay, and J. Banchereau of
Baylor Institute for Immunology Research and Sammons Cancer Center, Baylor
University Medical Center,Dallas, TX; and Department of Gene and Cell Medicine
and Department of Medicine, Immunology Institute, Mount SinaiSchool ofMedicine,
New York,NY,USA as published in Journal of Internal Medicine.

Also, a slide show / lecture presentation by Dr. Michael Morse on“Current
Status of Dendritic-Cell Vaccines” is available on the
Medscape site from WebMD as part of an educational session on “Therapeutic
Cancer Vaccines: Targeting the Future of Cancer Treatment” but requires
registration to enter the site.

What are dendritic
cells, and why are they useful?

Dendritic cells are in every person’s bloodstream and is a blood cell. They
normally function as an immune cell but are present in very small numbers,
somewhat like an elite force. Their usual function is to identify a foreign
substance, including cancer cells, and process the bits of such foreign
substances and then jumpstart the the immune response by bringing the foreign
substance to the attention of the rest of the immune system (mostly T
lymphocyte cells). The activated immune system is then able to circulate
throughout the body and destroy the cancer cells.

What kind of
cancers can be treated with Dendritic Cell therapy?

Theroretically all cancers can be treated, but experience tells us that
certain cancers such as melanoma and kidney cancer should respond best. To
date, therapeutic benefit has been documented in B cell lymphoma, myeloma,
melanoma, prostate cancer, colon cancer, ovarian cancer, breast cancer, and
renal cell cancer amongst others. If interested, patients should seek
professional advice on specific cancer and DC therapy and carefully weigh their
treatment options. There are currently active trials using DC therapy in melanoma
and kidney cancer.

At what cancer
stage should a patient consider Dendritic Cell therapy?

A patient can consider Dendritic Cell therapy when all other options have
been exhausted, or if the disease is stable and the patient is not on any chemo
or radiation therapies concurrently, or if the patient is free of disease but
at risk for recurrence and is seeking to potentially reduce the likelihood of
cancer reoccurrence. In general, patient should generally seek professional
advice on specific cancers and carefully weigh treatment options before
proceeding with specific therapy.

Can
leukemias/lymphomas be treated with Dendritic Cell therapy?

Research is now progressing in these areas, but patients should seek
professional advice on specific cancers and carefully consider their treatment.
(See review)

Can childhood
tumors be treated with Dendritic Cell therapy?

Yes, and experience is accumulating in this area. Patient’s guardians
should seek professional advice on specific cancers regarding DC therapy and
carefully weigh their treatment options (See review)

Can brain cancers
be treated with Dendritic Cell therapy?

Yes, and there are trials in this area at the present. Patients should seek
professional advice and weigh their treatment options. (See review)

Does one need to
have one’s own fresh or frozen tumor tissue available to do Dendritic Cell
Therapy?

Not always. Some trials require it and it is advisable to have tissue or
related antigen available if one is to do Dendritic Cell Therapy for
preventative purposes as there may not be sufficient tumor antigen in the
circulation for the Dendritic Cells to pick up. However, if patients with
advanced or metastatic disease, it is often possible to do “unloaded” Dendritic
Cell therapy, where naked Dendritic cells are injected intratumorally or into
the bloodstream where it would pick up antigens in vivo. One example of this
approach in treating pancreas and gallbladder cancer was presented in ASCO ’04.

How effective is
Dendritic Cell therapy in cancer?

Responses have generally been reported to be in the 20% range for heavily
pre-treated otherwise untreatable late stage patient, depending on the type of
cancer and the functional status of the patient. A larger percentage may not
experience remission as such but remain stable with treatment. If seriously
interested in the treatment, one should look into available trials, consider a
consultation with a reputable and knowledgeable physician or at a treatment
center to discuss prognosis and possible outcome as well as details relating to
the therapy.

Are any drugs or
procedures used as part of the Dendritic Cell Therapy?

Immune adjuvants are used to enhance or modulate the immune system during
Dendritic Cell therapy. Such agents may include cytokines such as IL-2, GM-CSF,
interferon; drugs such as ribavirin, thalidomide, low dose cyclophosphamide; as
well as keyhold limpet hemocyanin (KLH), Bacillus Calmette Guerein (BCG), QS21,
Montanide ISA-51. Procedures such as hyperthermia and ozone therapy are
sometimes used as adjuvants as well.

Is Dendritic Cell
Therapy safe?

Multiple early phases of Dendritic Cell therapy for cancer has been
completed and establishes the treatment as generally safe.

Are there any
contraindications to Dendritic Cell Therapy?

Recent radiation and chemotherapy which tends to depress the immune system
are relative contraindications to Dendritic Cell therapy. Immunologic testing
can better establish the condition of the immune system to help physicians
determine if a patient is a good candidate for Dendritic Cell therapy. Recent
blood transfusions, active autoimmune disease as well as pregnancy are also
possible contraindications. Contraindications should be carefully discussed and
reviewed with the consulting physician before proceeding.

Are there any
clinical trials I can take part in?

There are a number of domestic trials in the US as well as start-up
elsewhere in the world that you may qualify for, particularly for melanoma,
renal cell cancer, and other solid tumors and leukemias as well. You should
refer to our clinical trials section for more information to see if you are
eligible.

What if a patient
is not qualified for any active trials?

One can consider private treatment in Europe or elsewhere out of a trial
setting is one is not eligible for clinical trials. If seriously interested or
you need help in sorting out the pros and cons of various trials vs. private
treatments as well as the details of the actual Dendritic Cell therapy
protocols involved, one should consider a consultation with a reputable and
knowledgeable physician to discuss choice of trials, prognosis and possible
outcome as well as logistical details relating to Dendritic Cell therapy.

Is Dendritic Cell
Therapy an expensive treatment?

If one enrolled in a clinical trial, the treatment itself should be free.
If one opts to be treated privately, the treatment cost is comparable with
other forms of cancer therapies (eg chemotherapy or newer targeted molecular
therapies) and is generally under US 5,000 per treatment course depending on
the center.